Abstract
Phagocytic cells are the first line of innate defense against intracellular pathogens, and yet Toxoplasma gondii is renowned for its ability to survive in macrophages, although this paradigm is based on virulent type I parasites. Surprisingly, we find that avirulent type III parasites are preferentially cleared in naive macrophages, independent of gamma interferon (IFN-γ) activation. The ability of naive macrophages to clear type III parasites was dependent on enhanced activity of NADPH oxidase (Nox)-generated reactive oxygen species (ROS) and induction of guanylate binding protein 5 (Gbp5). Macrophages infected with type III parasites (CTG strain) showed a time-dependent increase in intracellular ROS generation that was higher than that induced by type I parasites (GT1 strain). The absence of Nox1 or Nox2, gp91 subunit isoforms of the Nox complex, reversed ROS-mediated clearance of CTG parasites. Consistent with this finding, both Nox1-/- and Nox2-/- mice showed higher susceptibility to CTG infection than wild-type mice. Additionally, Gbp5 expression was induced upon infection and the enhanced clearance of CTG strain parasites was reversed in Gbp5-/- macrophages. Expression of a type I ROP18 allele in CTG prevented clearance in naive macrophages, suggesting that it plays a role counteracting Gbp5. Although ROS and Gbp5 have been linked to activation of the NLRP3 inflammasome, clearance of CTG parasites did not rely on induction of pyroptosis. Collectively, these findings reveal that not all strains of T.gondii are adept at avoiding clearance in macrophages and define new roles for ROS and Gbps in controlling this important intracellular pathogen.IMPORTANCEToxoplasma infections in humans and other mammals are largely controlled by IFN-γ produced by the activated adaptive immune system. However, we still do not completely understand the role of cell-intrinsic functions in controlling Toxoplasma or other apicomplexan infections. The present work identifies intrinsic activities in naive macrophages in counteracting T.gondii infection. Using an avirulent strain of T.gondii, we highlight the importance of Nox complexes in conferring protection against parasite infection both in vitro and in vivo We also identify Gbp5 as a novel macrophage factor involved in limiting intracellular infection by avirulent strains of T.gondii The rarity of human infections caused by type III strains suggests that these mechanisms may also be important in controlling human toxoplasmosis. These findings further extend our understanding of host responses and defense mechanisms that act to control parasitic infections at the cellular level.
Highlights
Phagocytic cells are the first line of innate defense against intracellular pathogens, and yet Toxoplasma gondii is renowned for its ability to survive in macrophages, this paradigm is based on virulent type I parasites
We observed a similar enhanced clearance of the CTG strain in naive bone marrow-derived macrophages (BMDMs), while GT1 survived significantly better (Fig. 1B). This finding is somewhat surprising, as T. gondii is generally regarded as a pathogen that survives in naive macrophages, owing to its ability to actively invade the host cell and avoid phagocytic responses [4]
We found that highly avirulent type III strains are rapidly cleared in naive macrophages, even in the absence of interferon activation
Summary
Phagocytic cells are the first line of innate defense against intracellular pathogens, and yet Toxoplasma gondii is renowned for its ability to survive in macrophages, this paradigm is based on virulent type I parasites. ROS and Gbp have been linked to activation of the NLRP3 inflammasome, clearance of CTG parasites did not rely on induction of pyroptosis These findings reveal that not all strains of T. gondii are adept at avoiding clearance in macrophages and define new roles for ROS and Gbps in controlling this important intracellular pathogen. The major differences in mouse virulence among these strain types have been mapped to a polymorphic family of rhoptry kinases including ROP18 and ROP5 [16] These determinants have been shown to play a major role in combating host defense in gamma interferon (IFN-␥)-activated cells, where the acute virulence is attributed to their composite genotypes [17]. ROP18 has been shown to participate in defense against Gbps [31], the mechanism responsible for this activity is unknown
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